The aim of this proposal is to synthesize novel anti-HTLV- III/LAV/HIV agents. The agents contain an oligonucleotide or non-polar oligonucleotide analog tethered to an intercalating agent and are targeted to specific sequences on the retroviral RNA template, including the primer binding site and the transactivator, gag and pol genes. For example, a dodecadeoxyribonucleotide or analog complimentary to the primer binding site of HTLV-III/LAV/HIV will be prepared and linked via a tether to a benzophenanthridine alkaloid which also binds to the template primer. Other intercalating agents, including acridines and azido-acridines, will also be used. Various tether arms will link the intercalating agent to the oligodeoxyribonucleotide, providing information on the effect of the nature, length, and point of attachment of the linker arm on anti-viral activity. Projects 1 and 2 are directed at attaching the intercalating agents to the oligonucleotides and analogs. Project 3 will prepare the oligonucleotides and non-polar analogs. These projects will be supported by 4 cores: (1) An HTLV-III/LAV/HIV testing core; (2) A mechanism of action core; (3) A liposome encapsulation core aimed at delivering the polar compounds to cells and the virus; and (4) An animal testing core. The drugs synthesized in this project are expected to have any or all of the following novel properties: (1) Unique activity due to a synergistic effect of the oligonucleotide (or non-polar analog), the linker arm, and the intercalating agent; (2) Reduced degradation by exonucleases; and (3) An ability to covalently bind and modify viral RNA (in cases where the intercalating agent has a light activatable functionality).